TCF7L2, What this Very Common Type 2 Diabetes Gene Does

Many of you have been sold a bill of goods about how you "caused your diabetes" with unhealthy lifestyle choices. The media are full of articles telling us that diabetes is caused by obesity and failure to exercise which cause insulin resistance. You might have been told that while people with Type 1 Diabetes don't secrete insulin, people with Type 2 Diabetes secrete too much insulin. Though doctors repeat this misinformation, it turns out not to be true.

High quality research suggests very strongly that most Type 2 Diabetes results from genetic damage. This damage may be inherited or it may be caused by environmental pollutants like arsenic, PCBs, pesticides and popular prescription drugs. The environment of the womb can also permanently alter the expression of certain genes in ways that promote the development of Type 2 Diabetes.

Since the research has made it clear that most Type 2 is inherited, scientists have been using the new, cheap tools for studying the genome, to search for the gene variants that are common among people with Type 2 diabetes and absent in the rest of the population.

The single most common Type 2 Diabetes gene they've found in populations of people with Western European heritages is a variant of TCF7L2. A study published in this month's edition of the journal Diabetes sheds much light on why this gene is so closely associated with (i.e. causes) Type 2 Diabetes. You can find the study here:

TCF7L2 Variant rs7903146 Affects the Risk of Type 2 Diabetes by Modulating Incretin Action
Dennis T. Villareal et al. Diabetes Diabetes February 2010 vol. 59 no. 2 479-485, doi: 10.2337/db09-1169

First off, ignore the article's title. As is becoming more and more common, the titles of research studies are being slanted to appeal to whatever the fashionable belief of the year might be in diabetes research. And as is also common, that fashionable belief is heavily influenced by the mechanisms used by whatever new drugs are being peddled by Big Pharma. Since right now incretin drugs are the hottest (i.e. most expensive) new drugs, the researchers pitched this article as if it was a study documenting the effect of the defective TCF7L2 gene on incretin hormones. In fact, its results show something else entirely.

What the researchers did here was take eight subjects with the specific variant of the TCF7L2 gene that has been linked to Type 2 diabetes and compare them to a group of 10 controls lacking this gene variant. The tool used was a fancy 5 hour glucose tolerance test. (Yes, I know this is a pitifully small sample which makes its result suspect, and thanks for noticing.)

As described in the study the subjects:

underwent 5-h oral glucose tolerance test (OGTT), isoglycemic intravenous glucose infusion, and graded glucose infusion (GGI).

The isoglycemic infusion is one where glucose levels are maintained at a constant level. In the graded glucose infusion the glucose amount is raised in steps in amounts that are usually calculated as a function of the subject's body weight. This is because glucose raises blood sugar in inverse proportion to the subject's body weight: the more a person weighs, the less rise there is with each additional gram of glucose.

Note that the researchers made no direct measurement of the incretin hormones, GLP-1 and GIP in the course of the study. They drew their conclusions about incretin hormones after applying a mathematical model to the glucose tolerance test results.

As stated in the study:

The incretin effect was assessed from ratios of the insulin secretory rates (ISR) during oral and isoglycemic glucose infusions.

This strikes me as an odd way to determine the effect of incretin hormones. I'm sure the model was based on the findings of some other study, but without direct measurement of the incretin hormones the conclusion has to be labeled, at best, "speculative".

So let's ignore that for now, and see what we can safely conclude from this fancy glucose tolerance test. And it turns out that it is something worth noting. The study found that

β-cell responsivity to oral glucose was 50% lower (47 ± 4 vs. 95 ± 15 × 109 min−1; P = 0.01) in the group of subjects with risk-conferring TCF7L2 genotypes compared with control subjects.

This means the TCF7L2 gene carried by so many people with Type 2 diabetes damages the ability of the beta cell to secrete insulin in response to rising blood sugars.

If so, we can define TCF7L2-related Type 2 Diabetes as a disease of insulin insufficiency, NOT, as we are usually told, a disease caused by insulin resistance.

The headlined conclusion of this study, based on the estimates of "incretin effect" derived from the mathematical model is that:

The TCF7L2 variant rs7903146 appears to affect risk of type 2 diabetes, at least in part, by modifying the effect of incretins on insulin secretion. This is not due to reduced secretion of GLP-1 and GIP but rather due to the effect of TCF7L2 on the sensitivity of the β-cell to incretins.

This translates into saying that normal amounts of incretin hormones are being made, but the beta cell isn't responding to them. Given that this conclusion is drawn without any measuring of incretin hormone levels, the only part of this statement that is reliable is the "at least in part" which translates into, "Perhaps, maybe."

In any case, this is not the first study to find that the common genes associated with Type 2 Diabetes cause failure to secrete insulin, NOT insulin resistance. The more research done into these genes, the more the balance is shifting to finding that Type 2 Diabetes is often an insulin deficiency disease.

You can read about the research that had identified the common Type 2 Diabetes genes in this excellent summary:

NIH News: Newly Identified Genes Influence Insulin and Glucose Regulation: Five of these variants raise type 2 diabetes risk.

Note this extremely interesting statement from the lead researcher in this large scale effort to find Type 2 Diabetes genes:

"The hallmarks of type 2 diabetes are insulin resistance and impaired beta cell function. We were intrigued to find that most of the newly found variants influence insulin secretion rather than insulin resistance. Only one variant, near IGF1, is associated with insulin resistance," said lead author Inês Barroso, Ph.D., of the Wellcome Trust Sanger Institute, Cambridge, England.

You can read about much more research that links Type 2 Diabetes to genetic flaws both inherited and caused by environmental pollutants on the web page,

You Did Not Eat Your Way to Diabetes.

If you have been blaming yourself for causing your diabetes, I urge you to take a look at that page. You'll feel a lot better about yourself after you do.